Melanocyte-stimulating hormone is known to participate in the control of the colors of the skin and hair of humans and animals, and to darken the color of the human skin (e.g., Nature (1961) 189, 176-179). It is reported as the main cause of such action that melanocyte-stimulating hormone accelerates the growth of melanocytes and also activates tyrosinase which is an enzyme for the biosynthesis of melanin (Proc. Natl. Acad. Sci. (1995) 92, 1789-1793). On the other hand, it is known that melanocyte-stimulating hormone is produced by skin epidermal cells, and that the production amount is increased largely by the irradiation of ultraviolet rays (ACTH Relat. Rept. (1995) 6, 63-68). It is thought from these facts that melanocyte-stimulating hormone is the main cause of pigmentation after sunburn by ultraviolet rays.
As other actions of melanocyte-stimulating hormone, there are known an inhibitory action of the production of nitrogen monoxide by macrophages and an immunosuppressive action through IL-10 (e.g., Immunology Today (1997) 18, 140-145) and an appetite-controlling action (e.g., Am. J. Physiol. 274 Endocrinol. Metab. 37 (1998) E627-E633).
Accordingly, the suppression of the formation of melanocyte-stimulating hormone or the inhibition of the action thereof can realize the prevention of pigmentation to be caused by ultraviolet rays, the prevention, improvement or recovery of or from immune abnormality or immunodeficiency, or the regulation of body weight by appetite control.
Hitherto, there have been known as melanocyte-stimulating hormone inhibitors, His-D-Arg-Ala-Trp-D-Phe-Lys-NH2 (Peptides (1994) 15, 627-632), D-Trp-Arg-Leu-NH2 (Proc. Natl. Acad. Sci. (1995) 92, 2894-2898), and the like. However, these inhibitors all contain tryptophan which is an unstable amino acid, and therefore there is a problem that the stability during storage is inferior. Moreover, these inhibitors are known to decolor the skin of reptiles and the pigment cells of amphibians, but it has not been clarified whether they have the action of suppressing the formation of melanin and the activation of tyrosinase by melanocyte-stimulating hormone, which cause the pigmentation of the human skin.
Moreover, as other melanocyte-stimulating hormone inhibitors, it is known that an agcuti protein and fragment peptides thereof have a pigmentation inhibitory action (WO 97/00892), but there are problems that the production thereof is not facile and that the stability during storage thereof is inferior.
Furthermore, there are problems that some melanocyte-stimulating hormone inhibitors which even show effects of decoloring pigment cells, and the like, upon the evaluation with cells, exhibit only weak effects, and that the expression of the effects takes some period of time even though they exhibit effects such as the prevention of pigmentation, the prevention, improvement or recovery of or from immune abnormality or immunodeficiency, the regulation of body weight by appetite control, or the like, in the case of their actual application to living body.